Deep vein thrombosis (DVT) and subsequent post-thrombotic syndrome (PTS) are serious health concerns affecting numerous Americans each year. The open vein hypothesis postulates that rapid removal of venous thrombi is important for reducing PTS risk. Understanding the course of thrombus resolution is therefore critical for improved clinical management of individuals with DVT. Fibrin-the insoluble meshwork that provides support and stability to a clot-lies at the nexus of risk factors contributing to thromboss. Recent work by my lab has shown that hyperfibrinogenemia is causative in acute thrombosis. Importantly, hyperfibrinogenemia also increased resistance to thrombolysis in vivo. These findings support my global hypothesis that thrombus composition (fibrin content) influences the natural course of thrombus resolution. Preliminary data in an innovative model of thrombus resolution in the murine inferior vena cava suggest thrombus fibrin content modulates thrombus stability and lysis. These findings support two aims of investigation. First, using in vivo and in vitro models, I will determine how thrombus composition (fibrin content) dictates the course of thrombus resolution by testing two questions: 1) Does increased fibrin content delay return to patency in vivo? 2) Does increased fibrin content increase clot volume and decrease platelet clot retraction? Second, again using in vivo and in vitro models, I will determine how thrombus composition influences leukocyte function during thrombus resolution. I will test the following three questions: 1) Does increased fibrin content alter leukocyte recruitment to the clot? 2) Does increased fibrin content alter leukocyte function (secretion of cytokines or fibrinolytic mediators? 3) Does increased fibrin content alter leukocyte migration through the clot? Results from these experiments will elucidate mechanisms contributing to venous thrombus stability. These findings will advance the field by providing information on the role of thrombus composition in thrombus resolution, and identify targets for accelerating thrombus resolution. PUBLIC HEALTH RELEVANCE: Inappropriate blood clot formation (thrombosis) is the leading cause of death and disability in the Western world. The open vein hypothesis postulates that rapid removal of venous thrombi reduces the risk of post-thrombotic syndrome. Understanding the mechanisms that regulate the natural course of thrombus resolution is critical to develop approaches for preventing and managing this devastating disease.